What Is the Difference in Risk of Early Prostate Cancer Death Between Men at Higher vs Lower Genetic Risk?

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In a two-decade-long study published in JAMA Network Open, researchers analyzed the risk of early prostate cancer death among men with higher versus lower genetic risk, using data from two prospective cohort studies in Sweden and the United States of America (US).

They found that men with higher genetic risk had significantly increased rates of early and late prostate cancer mortality, with one-third of these early deaths predicted to be preventable through healthy lifestyle behaviors.

Study: Early Prostate Cancer Deaths Among Men With Higher vs Lower Genetic Risk. Image Credit: NTshutterth/Shutterstock.com


Despite advances in early diagnosis and treatment, prostate cancer continues to be a leading cause of cancer death among men, with approximately 400,000 annual deaths globally. Notably, one-third of these deaths occur before age 75 years, highlighting the need for new prevention approaches.

Targeting high-risk populations, including men with a high polygenic risk score (PRS), offers a promising approach. PRSs effectively stratify prostate cancer risk and mortality. Combining PRS with family history or rare variant measurements can enhance risk assessment.

While established risk factors are nonmodifiable, lifestyle behaviors like maintaining a healthy weight, not smoking, and regular physical activity may reduce the risk of prostate cancer progression and death, particularly in high-risk individuals.

However, the extent to which targeted prevention strategies can reduce premature prostate cancer deaths remains unclear.

Therefore, researchers in the present study analyzed data from two prospective cohort studies to assess the impact of genetic risk on early mortality and the effect of a healthy lifestyle on preventing prostate cancer.

About the study

Data from the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS) were analyzed.

The MDCS and the HPFS included 10,270 and 9,337 genotyped men from Sweden and the US, respectively, without prostate cancer and with lifestyle data. The median age at the start of follow-up was 59 years in MDCS and 65.1 years in HPFS.

A healthy lifestyle was defined using a score based on not smoking, maintaining high physical activity, a healthy weight, and a diet rich in tomato products and fatty fish while low in processed meat.

This score categorized lifestyles as healthy (3-6 points) or unhealthy (0-2 points), with an additional detailed 4-group categorization and a sensitivity analysis incorporating various dietary recommendations.

Genetic risk was classified as high or low based on a multi-ancestry PRS of 400 variants for prostate cancer relative to a median value and a family history of cancer.

Prostate cancer-specific deaths were tracked via the Swedish Cause of Death Register (MDCS) and the National Death Index, supplemented by next-of-kin reports.

Early deaths were defined as those before age 75, late deaths as those after age 75, and lifetime risk included deaths up to age 85. Statistical analysis involved Cox regression, inverse-probability weighted models, and regression, pooled by fixed-effects meta-analysis.

Results and discussion

As per the study, 67% of men were classified as having higher genetic risk based on PRS and family history, with about 30% having a lifestyle score indicating unhealthy behaviors.

During a median follow-up of 24 years in MDCS and 23 years in HPFS, 444 prostate cancer deaths were recorded before (107) and after age 75 years (337). Higher genetic risk was linked to a threefold increased rate of early and twofold increased rate of late prostate cancer death.

Unhealthy lifestyles notably elevated risk only among higher genetic risk men, particularly with smoking and BMI ≥30. Cohort-specific results were found to be consistent.

Men at lower genetic risk were found to have low lifetime risks of prostate cancer death ranging from 0.6% to 1.3%, with no clear pattern by lifestyle. However, higher genetic risk groups showed significantly higher lifetime risks for combined higher genetic risk men (2.3% to 3.1%).

For those in the PRS 50–75% category (1.8% to 2.9%), increasing further for men in the PRS 75–100% category (3.1% to 4.9%) category across both the studies. A majority of prostate cancer deaths occurred among men with higher genetic risk, accounting for 88% of deaths by age 75 years.

Lifestyle changes could prevent 22% to 36% of these deaths before age 75 years among higher genetic risk men. Alternative dietary factors suggested preventability estimates up to 39%.

The study is strengthened by including two large, independent cohorts with 20 years of follow-up, showing consistent results across different populations. However, the analysis is limited by potential differences in prostate cancer testing and treatment, consideration of factors only at study entry, and the inclusion of men of European ancestry alone.


In conclusion, this study indicates that prostate cancer prevention strategies should focus on men with a high genetic risk.

About one-third of early prostate cancer deaths in men with genetic risk may be preventable through healthy lifestyle choices or by ensuring equal access to early detection and optimal treatment.

Targeted interventions for high-risk men could significantly lower the number of premature deaths from prostate cancer.

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